Gastro esophageal reflux disease (GERD) impacts the lives
of over 20% of Americans, and it is one of the most common
reasons for patient visits to both gastroenterologists and primary
care physicians [1]. GERD affects patients' quality of life, work
productivity and thus, posses a significant financial burden on
community. Untreated GERD can lead to multiple complications
including esophagitis, Barrett's esophagus, esophageal stricture
and esophageal cancer [2].

Lifestyle modification and medical therapy including acid
suppressive medications such as H2 blockers and proton pump
inhibitor (PPI) are the first-line treatment for GERD [2]. With the
invention of the PPI, GERD treatment success has significantly
improved. Nonetheless, approximately 30-40% of patients
are not adequately treated with medical management [3]. In
addition, medication management commits patients to lifelong
medications, and their potential long-term side effects, including
osteoporosis, vitamin and mineral malabsorption including
B12 and iron deficiency, increased infection risk, heart attacks,
chronic kidney disease, dementia and others by observational
studies [4-6]. These pharmacovigilance observational studies
have identified associations, not causation. Yet, this has caused
concern for both physicians and patients.

Laparoscopic anti reflux surgeries (LARS) have been the
gold standard for surgical treatment for patients who have
failed medical treatment. Less than 1% of the patients who have
failed medical treatment undergo laparoscopic fundoplication.
Consequently, a significant number of patients with inadequately
treated reflux symptoms persist [7]. Laparoscopic fundoplication
is invasive, requiring hospitalization, and carries the risk of
post-op complications including dysphasia, diarrhea, and gas
bloat syndrome. Approximately 50-60% of patients continue to
require PPI 5 to 10 years post operation [8].

Although multiple minimally invasive endoscopic procedures
including sewing, trans mural fasteners, endoscopic stapler,
Enteryx (Boston Scientific, Boston, MA, USA), Gatekeeper reflux repair system (Medtronic, Inc., Minneapolis, MN, USA) have been
investigated over the last two decades, and they have not been
in current clinical use as a result of procedure complications and
limited effectiveness [9]. Trans oral Incision less Fundoplication
using the EsophyX device, radiofrequency energy treatment to
lower esophageal sphincter using Stretta, and the partial anterior
fundoplication using the Medigus Ultrasonic Surgical Endostapler
(MUSE), are three endoscopic procedures that have been tested
by prospective studies, found to be effective, approved by the
United States Food and Drug Administration (FDA), and able to
treat the patients that are found to be in the treatment gap of
patients with chronic GERD. In this review, we will summarize
the FDA approved Trans oral Incision less Fundoplication,
Stretta, and muse.

Trans oral Incision less Fundoplication

Trans oral Incision less Fundoplication (TIF) using the
EsophyX device is an endoscopic procedure that performs a
partial (270 degree) fundoplication. It operates under the same
anatomical principles of surgical fundoplication, performed
endoscopically instead of surgically. The EsophyX device (Endo
Gastric Solutions, Inc., Redmond, WA, USA) became available in
the United States in 2007 [10]. The device and procedure has
been updated over the years. The most updated procedure,
described as TIF-2, came to market in 2009. The goal of the
procedure is to recreate the gastro esophageal valve and thereby
reduce the symptoms of gastro esophageal reflux [11].

Currently, the procedure is usually performed under general
anesthesia in the outpatient setting with possible short postprocedure
inpatient observation. The EsophyX device (Figure
1, Figure 2) is placed on the endoscope. The endoscope is then
inserted under direct visualization through the mouth and into
the stomach. The endoscope is advanced and retroflexed to
obtain direct visualization of the procedure. The tissue retractor
is used to grasp the fundus, pull it into the EsophyX device,
thereby recreating the gastro esophageal valve. If a hernia less
than 2cm is present, the endoscope and device can be advanced
to reduce the hernia. After the valve is created and hiatal hernia (if present) reduced, the wrap is created by the tissue mold and
H-shaped polypropylene fasteners are deployed to hold the
tissue in position (Figure 3). Additional fasteners are deployed
to create a 2-3cm, 200-300-degree fundoplication [12-14].

Multiple studies evaluating the TIF procedure has been
completed [10,15-17]. Results vary and most studies have
been small with short term follow up and changes in the device
and technique over time. With improvements in device and
technique, the results of the procedure have also improved.

Two recent trials evaluating TIF procedure are discussed
below. First, the RESPECT trial completed by Hunter and
colleagues was a prospective, sham-controlled trial. One hundred
seventeen patients with GERD without significant hiatal hernia
(>2 cm) were randomized to sham procedure or TIF (80 patients
to the TIF and 37 to the sham, PPI arm). Patients were followed
over a 6-month period. TIF was ultimately found to significantly
reduce (P=0.023) regurgitation in 67% of patients as compared
to only 45% in the sham, PPI arm. In addition, esophageal pH
improved after TIF – mean of 9.3% before TIF and 6.3% after TIF.
The sham, PPI arm showed no significant improvement – mean
8.6% before sham and 8.9% after sham. The authors ultimately
concluded that TIF was an effective treatment up to 6 months
after the procedure for patients with refractory GERD despite
PPI treatment [15].

A second recent publication, the TEMPO trial by Trad, et al.
completed a 6-month multicenter randomized study comparing
the efficacy of TIF against PPI in controlling GERD symptoms. Sixty
patients (39 = TIF, 21 = PPI) participated in the study. Patients
in the PPI group were started on maximum dose PPI. The other
arm comprised of patients undergoing TIF with EsophyX (TIF-2).
At 6 month follow up, 97% of patients experienced elimination
of regurgitation as compared to 50% in the PPI arm. In addition,
90% of patients in TIF arm had eliminated PPI use [16].

As mentioned previously, most of available publications
evaluating the efficacy of TIF are short-term studies. One study
by Testoni, et al., evaluates the long term efficacy of TIF over a
6-year period. Fifty patients were evaluated during the study – at
6 and 12 months, 45 at 24 months, 32 at 36 months, 24 at 4 years 19 at 5 years and 14 at 6 years. 75-80% of patients stopped
or halved their PPI use at 3 years and this remained stable up
to 6 years. In addition, symptom scores were lower while off
PPI. More objectively, significant improvement in impedance
monitoring (p=0.01) was noted with fewer acid refluxes after
the TIF treatment [16]. Witteman, et al also performed a study
noting significant improvement in GERD symptoms scores and
esophageal acid exposure at 6 months. At 12 months, symptoms
scores remained improved but esophageal acid exposure no
longer showed improvement [10].

In summary, TIF has emerged as a safe, effective, and durable
alternative to refractory GERD patients with small hiatal hernia
(>2 cm) without significant adverse events.

Stretta
The FDA approved Stretta (Mederi Therapeutics, Greenwich,
CT, USA) in 2000. An updated clearance on the radiofrequency
(RF) generator was issued 2011. The Stretta device is comprised
of aRF generator and a flexible balloon catheter assembly with a
four nickel-titanium needle system to deliver energy (465 kHz,
2-5 W per channel, 80 V maximum).

The procedure is performed under sedation, usually with
intravenous propofol in an outpatient setting. During the Stretta
procedure, an endoscope is introduced through the mouth and
into the esophagus. To obtain proper electrode placement, the
distance from the incisors to the squamocolumnar junction
(Z-line) is measured and a guide-wire is placed. Subsequently,
the endoscope is removed and a catheter with four needleelectrodes
(Figure 4) is advanced through the mouth over the
guide-wire into the esophagus. Using the four needle-electrodes,
radiofrequency energy is delivered to the muscularispropria
with a target temperature of 85OC for 60 seconds. Maintaining
tight temperature control prevents mucosal heat injury and
stricture formation. Multiple treatments are applied by rotating
the catheter circumferentially and advancing the catheter from
1cm proximal to the z-line and distally 2cm to the gastric cardiac.
A total of 56 treatments are applied with an average procedure
time around 35-minute (Figure 5) [18-20].

The exact mechanisms of action of Stretta are not well
understood. Four mechanisms have been proposed and are
supported by several studies. These four mechanisms are:
increased gastric yield pressure, increased thickness of the lower
esophageal sphincter muscle, decreased gastro-esophageal
junction compliance without fibrosis, and decreased transient
esophageal sphincter relaxations. Each of these proposed
mechanisms supports the ultimate goal of re-enforcing the antireflux
barrier [21].

It is interesting to note that Stretta has been shown to improve
gastro paresis in some patients. In 2008, Nora, et al, performed
a study that showed significant improvement of gastric emptying
at 30 min, 60 min, and 90 min and 120 min intervals 6 months
after the Stretta procedure. All of these patients had a 1-year
symptoms follow-up assessment, which showed significant

improvements in GERD related quality of life, dyspepsia and
heartburn sources [22]. However, these important findings will
need to be confirmed by the other investigators.

The safety data of the procedure has been documented in
several clinical trials and the over 15,000 procedures performed
[23]. The most common complications observed include
fever and chest discomfort, both self-limited. More serious
complications of esophageal perforation and death due to
aspiration pneumonia and bradyarrythmia have been described.
Overall, the safety profile for the Stretta procedure is acceptable
with less than 1 percent significant complications [24].

As Stretta has been available since 2000, multiple studies
of variable quality, methodology and outcome measures have
been completed with some conflicting outcomes. Despite these
inconsistencies, Stretta has been shown to be effective in three
randomized trials and over 40 other prospective clinical studies
[25]. In addition, the Society of American Gastrointestinal
Endoscopic Surgeons supports Stretta as an effective treatment
for refractory GERD patients [26].

Two recent selected studies that shed light on Stretta will be
discussed. First, Noar, et al, performed a study evaluating the 10-
year effect of Stretta. Notably, previous studies only demonstrated
the effectiveness of Stretta up to 4 years, whereas the Noar study
examined the effectiveness of Stretta up to a 10 year period. The
Noar study evaluated 217 patients with a primary outcome of normalization of the GERD-health-related quality of life (GERDHRQL)
in more than 70% of patients. Of the patients studied,
72% achieved the primary outcome. Secondary outcomes
included 50% reduction/elimination of PPI use and 60% or more
improvement in satisfaction at 10 years. Success was determined
by achievement of at least 50% of patients. The study found that
64% of patients achieved the secondary outcomes of reduced
PPI use, 41% of patients achieving complete elimination of PPI
use. The study also noted a reduction in pre-existing Barrett's
metaplasia from 33 patients at the onset of the study and only
5 at the conclusion of the study – an 85% reduction [27]. This
important finding needs to be confirmed by other investigators.

A second publication, a double-blind randomized cross-over
study of Stretta and sham treatment was completed by Arts,
et al in 2012. Symptom assessment, endoscopy, manometry,
24 hour pH monitoring and a dispensability test of the gastroesophageal
junction were performed at the study start and at
the study conclusion three months later. Twenty-two patients
were evaluated – 11 from each arm. The study determined
that there were no changes in esophageal acid exposure and
lower esophageal sphincter pressure at 3 months post Stretta
procedure. Symptom score was significantly improved for
patients undergoing the Stretta procedure. Symptom score
improved from 14.7+/-1.5 to 8.3+/-1.9 after the initial Stretta
procedure and did not significantly change after the sham
procedure. In the initial sham procedure arm, the symptom score
did not significantly improve after the initial sham treatment
(16.1 +/-2.5 versus 15.6 +/-2.2) but did improve after treatment
with Stretta (16.1+/-2.5 versus 7.2+/-1.6) [28].

As mentioned previously, multiple studies of variable quality,
methodology and outcome measures have been completed with
conflicting outcomes. A systematic review and meta-analysis was
performed by Perry, et al in 2012. A total 1441 patients from
18 studies were included and determined that radiofrequency
ablation to the lower esophageal sphincter does produces
significant improvement on reflux symptoms [19]. On the other
hand, a recent systemic review and meta-analysis evaluating 165
patients from 4 trials showed no significant evidence for efficacy
of Stretta in the treatment of GERD. The study recommends
the need for a large, randomized control study to conclusively
address the efficacy of Stretta for the treatment of refractory
GERD [29].

Medigus Ultrasonic Surgical Endostapler (MUSE)

Similar to TIF, MUSE is an endoscopic stapling system that
creates an endoscopic partial fundoplication. That being said,
the MUSE apparatus differs significantly when compared to the
EsophyX device.
The MUSE device consists of a single use flexible surgical
endostapler with video capability, ultrasonic sight with aligning
screws, and stapling anvil (Figure 6). The procedure is performed
by initially placing an over tube using standard technique. The
MUSE device is then inserted through the over tube and into
the fundus of the stomach. The endostapler is then retroflexed and pulled back until the staple cartridge is 3cm proximal to the
GEJ. The stomach mucosa is then clamped between the stapling
cartridge and stapling anvil. Using the aligning screws and
ultrasonic sight, alignment is confirmed and staples are deployed.
The MUSE device is then rotated and the procedure repeated
two additional times to achieve a 180° anterior fundoplication
(Figure 7).

The efficacy of MUSE is based upon the data from a multicenter
prospective trial by Zacherl, et al. The trial evaluated
69 patients at six sites over a 6-month period who underwent
fundoplication with MUSE. A total of 66 patients completed the
6-month follow up. A total of 48/66 (73%) of patients had a
greater than 50% improvement in GERD health-related quality
of life (HRQL) off PPI. A total of 42/66 (64.6%) were no longer
using a PPI daily [30]. A follow up study from the initial clinical

trial was performed by Kim, et al. If evaluated 37 patients at 4
years post-procedure. A total of 25/36 (69.4%) of patients were
off PPI. In addition, the GERD-HRQL continued to be significantly
decreased at 4-year follow up [31].

In the trial performed by Zacherl, et al, the most common
adverse events were chest discomfort in 16/72 patients (22%)
and sore throat in 15/72 patients (21%). A total of 8 serious
adverse events (SAEs) were reported – 4 mild, 2 moderate and
2 severe were seen in first 24 patient. The two severe SAEs
included one case of empyema and pneumothorax requiring
chest tube placement and hospitalization and the second case a
gastrointestinal bleed requiring transfusion. The two moderate
SAEs included complications of pneumomediastinum and
pneumoperitoneum requiring only antibiotics, no additional
intervention. Subsequent interim review of the early SAEs
resulted in protocol changes and device changes. Protocol
changes included increase in the number of staples deployed,
prophylactic therapy to reduce retching post-procedure, and
a post-procedure chest X-ray to ensure no leaks are present.
Device changes were made to prevent air insufflation during
screw insertion to prevent pneumo peritoneum. These changes
resulted in no additional cases of leak or pneumo mediastunum
in the subsequent 48 patients [30].

Conclusion

In conclusion, TIF, and Stretta, and MUSE are treatment
options for patients with refractory GERD. They provide long
sought after minimally invasive endoscopic options to treat
patients found in the treatment gap between proton pump
inhibitors and fund application. MUSE appears to be safe and
effective according to the initial multi-center prospective trial,
but additional studies will need to be performed. Having been
tested by multiple studies, TIF and Stretta have proven their
effectiveness as potential treatment options that should be
incorporated into the armory of gastroenterologists and selected
surgeons.